Liver Phnysiology 4- Protein Synthesis And The Urea Cycle In Liver Disease Flashcards
Amino acids
Amino acids surplus to requirement for protein synthesis can be metabolized to non-nitrogenous substances, such as glucose, glycogen or fatty acids, or they can be oxidised to generate ATP
On the other hand, during fasting or starvation
Catabolic wasting of muscle occurs, thereby yielding amino acids which are used for gluconeogenesis so as to maintain normoglycaemia
Because the ammonia derived from these amino acids is extremely toxic, it is converted to non-toxic urea for urinary excretion.
Any ammonia which evades detoxification as urea can alternatively be incorporated into glutamine by glutamine synthetase, which has been described by Haussinger as serving as a scavenger for stray ammonium ions
Glucose alanine cycle
In muscle, alanine is the principal ammonia scavenger and transporter. Glutamate collects the ammonia, the enzyme alanine aminotransferase (ALT) transaminates the amino group from glutamate, forming α ketoglutarate, and the amino group gets attached to pyruvate, formed from glycolysis, making alanine
This gets transported in the blood, taken up by the liver where the reverse reaction occurs and the ammonia gets converted to urea
Pyruvate is recycled into glucose
Solving 2 problems with 1 cycle
Moving carbon atoms of pyruvate, as well as excess ammonia, from muscle to liver as alanine.
Then in the liver, alanine yielding pyruvate – the starting block for gluconeogenesis, and releasing ammonia for conversion into urea.
The energetic burden of gluconeogenesis being imposed on the liver rather than muscle, so that muscle ATP can be devoted to muscle contraction.
Urea cycle
Arginine either from the diet or protein breakdown, is cleaved by arginase, generating urea and ornithine
In subsequent reactions a new urea is built on the ornithine (from ammonia and CO2 ) making citrulline
This, in turn, is reconfigured into arginine. The enzymes responsible for this are found partly in the mitochondria and partly in the cytosol (like glutaminase/glutamine synthase).
The reactions of one turn of the cycle consume 3 ATP equivalents and a total of 4 high energy nucleotide PO4=.
Urea is the only compound generated by the cycle: all other components are re-cycled.
The energy consumed by urea production is generated in the production of the cycle intermediates
Control of the cycle is via up or down regulation of the enzymes responsible for urea formation
So with long term changes in the quantity of dietary protein, upregulation in the order of 20 times has been demonstrated.
This can be due to either increased intake as with body builders – high protein low fat diets - or in starvation because muscle proteins are being broken down with the amino acid carbon skeletons providing the energy.
Thus the amount of ammonia that must be excreted increases
Fumarate produced in the cytosol by argininosuccinate lyase of the urea cycle enters the citric acid cycle in the mitochondrion and is converted in several steps to oxaloacetate
Oxaloacetate accepts an amino group from glutamate by transamination, and the aspartate thus formed leaves the mitochondrion and donates its amino group to the urea cycle in the argininosuccinate synthetase reaction
Intermediates in the citric acid cycle are boxed
Blocks in the urea cycle after CPS1 can cause accumulation of intramitochondrial CP.
This diffuses into cytosol and enters de novo pyrimidine synthetic pathway where orotate is an intermediate to uridine 5’ monophosphate
Raised in OTC, ASS (citrullinaemia), argininaemia
Amino acids, whether of dietary or endogenous (muscle) origin, enter the pathway of urea synthesis by
transdeamination route or the transamination route
Transdeamination route:
Initial transamination in the cytosol, followed by deamination in the mitochondrion
Alpha-ketoglutarate accepts an amino group from the donor aminoacid to form glutamate in a cytosolic reaction catalysed by an aminotransferase
The glutamate is then transported by the glutamate carrier into the mitochondrion where it is oxidatively deaminated by glutamate dehydrogenase to form alpha-ketoglutarate and ammonium ions
The ammonium is incorporated into carbamoyl phosphate, which in turn reacts with ornithine to enter the urea cycle as citrulline
Transamination route:
Alternatively nitrogen from the aminoacids can enter the urea cycle via the transamination route, which involves two transamination reactions
Again, alpha-ketoglutarate initially accepts the amino group from the donor amino acid and once again glutamate is formed (as above).
However, a second transamination now follows, with oxaloacetate accepting the amino group from glutamate to form aspartate in a reaction catalysed by aspartate aminotransferase (AST)
This aspartate now carries the second amino group into the urea cycle by condensing with citrulline to form argininosuccinate
Argininosuccinate is then cleaved to form fumarate and arginine
Finally arginine is hydrolysed to ornithine and urea, and ornithine is regenerated for another rotation of the cycle.
Major proteins produced by the liver
Albumin
Clotting Factors
What is Albumin?
Single polypeptide protein MW 66000
9-12g produced by the liver each day
Possible to increase this threefold
Leaves circulation via interstitium
Collected by lymphatics
Returned via thoracic duct
Rate known as the Transcapillary Escape Rate
The Starling Equation
NDP = Kf x [(Pc-Pi)-rc(pc-pi)]
Kf = filtration coefficient
Pc = capillary hydrostatic pressure
Pi = interstitial hydrostatic pressure
rc = reflection coefficient
pc = capillary oncotic pressure
pi = interstitial oncotic pressure
